Pharmacokinetics & Pharmacodynamics

Question 1

pharmacokinetics

Answer 1

how conc. of drug changes in body with time

Question 2

ADME

Answer 2

absorption
distribution
metabolism
elimination

Question 3

clinical aim of drug administration

Answer 3

achieve effective drug conc. (in therapeutic range) at site of action (systemic circulation) long enough to have an effect

Question 4

therapeutic window vs index

Answer 4

window refers to population while index refers to individual patient
wider box - wider range so safe

used to use LD50 (conc that kills 50% population) divided by ED50 (effective dose)
but not ethical

Question 5

bioavailability

Answer 5

proportion of dose of unchanged drug that reaches site of action

Question 6

intravenous injection

Answer 6

100% bioavailability because straight to systemic circulation
need sterile equip, trained, expensive, painful

Question 7

oral route (plus and minuses)

Answer 7

safest, most convenient, economical, always less than 100% bioavailability because destroyed by bacteria/acid/food/enzymes
absorption depends on rates of passage
some side effects and requires patient co-operation

Question 8

drug absorption from GI tract to circulation

Answer 8

Fick’s law of passive diffusion

rate = (permeability x SA x conc diff) / thickness of membrane

Question 9

what does permeability of drug depend on?

Answer 9

its lipid solubility

lipid soluble and small will pass better

Question 10

most drugs are….

and what is better absorbed?

Answer 10

weak acids/bases and unionised drugs are better absorbed

Question 11

other absorption methods

Answer 11

active transport
ion-pair absorption (+ve ion with -ve ion in gut forms neutral complex moves into blood)
pinocytosis engulfs
solvent drug (highly lipid soluble drug won’t dissolve in lumen so dissolve in solvent before drink)

Question 12

sites of drug absorption

Answer 12

little absorption: small intestine (main site), stomach, colon

Question 13

formulation

Answer 13

strong enough so don’t fall apart when handle but still dissolve

Question 14

gut motility

Answer 14

gastric emptying modulated by meal size/composition, drugs, physiological state (lay/sit), migraine

Question 15

orally administered drugs with potential problems

Answer 15

phenoxymethyl penicillin - absorbed by food so take on empty stomach
tetracyclines - absorption reduced by milk/antacids/iron
aspirin - iritate stomach

Question 16

1st pass metabolism

Answer 16

before systemic

Question 17

if drug rapidly metabolised by liver/gut then other routes?

Answer 17

inhalation - avoids 1st pass metabolism, straight to systemic

transdermal - across skin, hard to get across e.g. nicotine patches, ibuprofen gel

buccal+sublingual - gum+under tongue, straight to systemic

intranasal

rectal

subcutaneous - upper dermis not in muscle

intramuscular injection - large blood flow in muscles so reliable route, but can’t self administer

Question 18

penicillin administration

Answer 18

route affect bioavailability
oral - slow
IV - fast
IM - fast and longer duration
P-IM - modified IM with much longer duration

Question 19

plasma protein binding (function, free drug, what binds what, saturation of binding

Answer 19

drugs in plasma bound to proteins which act as buffer/carrier
only free drug is active and eliminated but free can cause toxic effects

weak acids bind plasma albumin
weak bases bind acid glycoprotein

saturation of binding is non linear relationship between dose and free conc.
a small increase in drug conc. causes large increase in free drug so toxic

Question 20

tissue distribution of drug depends on….

Answer 20

depends on lipid solubility, plasma protein binding and molecular weight
e.g. heparin is big so doesn’t leave plasma

Question 21

blood brain barrier

Answer 21

hard to get drugs into brain, and it pumps drugs out to have low conc.

because layer of tightly joined endothelial cells, contain P-glycoprotein (Pgp) efflux pump

lipid soluble drugs by passive diffusion
water soluble by carrier mechanisms

Question 22

drug metabolism in liver by hepatocytes (what happens, and explain process)

Answer 22

some converted to inactive metabolites
some to active metabolites
some excreted unchanged

Phase 1 (primary metabolites): transform molecular structure of drug

Phase 2 (secondary metabolites): conjugation - attachment of endogenous substance to original drug or after phase 1, by transferases

to increase water solubility, make polar, abolish activity

then excretion

Question 23

excretion

Answer 23

renal route via kidney

can change urinary pH to aid excretion
some drugs actively excreted like penicillin

dangerous if drug excreted unchanged

Question 24

other routes of excretion

Answer 24

biliary into intestine - bile to gal bladder to small intestine so can absorb back into blood - enterohepatic circulation

saliva, sweat, tears, expired
breast milk - danger to baby

Question 25

Vd

Answer 25

apparent (not real) volume of distribution not real because some conc. of drug in plasma so small that tells you large volume than humans have so just tells you if distributed in tissues or plasma

Question 26

fraction extracted

Answer 26

E= (conc in - conc out)/ conc in

Question 27

clearance

Answer 27

how well gets rid of drug rate of elimination/conc of input volume/time (virtual volume of blood cleared of drug per unit time)

Question 28

creatine clearance rate

Answer 28

linear relationship between drug clearance and creatine clearance so high conc in blood means poor clearance better than taking periodic blood samples to see drug conc change

Question 29

measuring clearance

Answer 29

creatine clearance blood sample renal clearance - urine samples

Question 30

normal clearance for healthy

Answer 30

88-128 mL/min women | 97-137 mL/min male

Question 31

clearance and age

Answer 31

decreases with age so half life of drug goes up and need to adjust dosage intervals

Question 32

first order elimination kinetics (most drugs)

Answer 32

rate of elimination proportional to drug conc. - exponential so faster elimination more drug

Question 33

kel

Answer 33

elimination rate constant units time-1 proportion of drug eliminated per unit time kel= rate of elimination/amount left

Question 34

time constant

Answer 34

1/kel | time taken for conc. to fall 1/e (37%)

Question 35

half life

Answer 35

time taken for drug conc to fall by half ln2/kel helps determine dosage interval

Question 36

2 exponentials of elimination

Answer 36

distribution to other compartments then slower rate elimination both 1st order kinetics

Question 37

Ka

Answer 37

absorption rate constant

Question 38

phases of drug in body

Answer 38

lag time (time to get to blood) absorption (plasma conc builds up) elimination (eliminate/distribute)

Question 39

area under curve of plasma conc (y) against time after ingestion (x)

Answer 39

AUC | bioavailability of drug so amount absorbed

Question 40

loading dose

Answer 40

injection to start then orally maintain level of conc. | better than oral when need immediate effect

Question 41

continuous infusion

Answer 41

slowly build conc. of drug over time (rapid is bad for BP) with infusion/pump to eliminate troughs in oral graph so get smooth curve and eliminate toxicity if use loading dose

Question 42

zero order kinetics

Answer 42

rate of elimination not proportional to drug conc but is constant e.g. ethanol if you start with more drug it takes longer to remove it so half life is not constant but depends on starting conc. so constant amount eliminated

Question 43

drug dosage changes

Answer 43

neonates have reduced body volume and higher proportion of water so reduce dose reduce dose in elderly because higher fat than water, drug binding to plasma proteins reduced low renal function and clearance at birth and reduced in elderly lower metabolism

Question 44

drug monitoring

Answer 44

monitor conc level in blood if toxic/effective take sample at peak conc./trough conc./time above threshold value

Question 45

urine sample to monitor drug

Answer 45

useful so don't need blood and for drugs partially/fully eliminated in urine but volume variable because how much drink so can't use drug conc. but absolute amount (moles)

Question 46

drug modes of action

Answer 46

``` enzyme inhibitors enzyme false substrates receptor activators receptor blockers ion channel blockers ion channel modulators neurotransmitter uptake blockers ```

Question 47

measuring response

Answer 47

force of contraction, current, change in potential, amount of 2nd messenger (cAMP), loss of NT, physiological change

Question 48

EC50

Answer 48

conc that gives 50% of max response

Question 49

why is there a max response?

Answer 49

finite no. receptors so all occupied | or property of tissue/cell so can't contract any more because max reached

Question 50

affinity

Answer 50

how well drug binds receptor (not about the response)

Question 51

efficacy

Answer 51

measure of response - how well turns receptor on to active form low means can't reach max response

Question 52

potency

Answer 52

combine affinity and efficacy

Question 53

k+1 | k-1

Answer 53

association rate constant | dissociation rate constant

Question 54

Kd

Answer 54

conc. of drug required to occupy 50% receptors (k-1)/(k+1) lower Kd means less drug needed so high affinity

Question 55

measuring affinity

Answer 55

can't measure contraction because measures efficacy as well ligand binding assay - radio label ligand and shows when bind to receptor so radioactive shows how much bound but must account for non-specific binding

Question 56

non-specific binding

Answer 56

low affinity so keeps binding and doesn't reach max - straight line saturate with cold ligand (without label) so any radioactivity is binding to non-specific sites so subtract off total binding to get specific binding

Question 57

desensitisation/tachyphylaxis

Answer 57

bound for long time to phosphorylated and receptor internalised so less response because less receptors or run out of mediators tachyphylaxis is whole organ or tissue no longer responds

Question 58

clinical agonists

Answer 58

adrenaline - increase HR and force contraction for anaphylactic shock (allergy) salbutamol for asthma dopamine increase HR morphine for severe pain

Question 59

partial agonsts

Answer 59

partial response same affinity but not full response conc. doesn't matter e.g. to reduce over-activity but not block basal activity, e.g. pain killer or treat addicts

Question 60

basal activity (constitutive)

Answer 60

receptor's activity in absence of ligand

Question 61

partial beta agonists

Answer 61

beta-blockers slow heart but don't block all beta receptors

Question 62

inverse agonists

Answer 62

reduce basal activity of G-protein receptors (reduces response below 0) many antagonists are inverse agonists

Question 63

GABA-A receptor

Answer 63

main inhibitory receptor in brain control excitation 2 binding sites for Gaba, 1 for barbiturates B2 full agonist binds to separate site to increase opening when GABA binds (inverse agonists would bind here and decrease opening)

Question 64

barbiturates

Answer 64

A barbiturate is a drug that acts as a central nervous system depressant and can therefore produce a wide range of effects, from mild sedation to death.

Question 65

competitive antagonists

Answer 65

binds to receptor but doesn't do anything but prevent agonist binding so no response enough agonist can outcompete antagonist don't change max response but shift curve to right because more conc needed for 50% response

Question 66

measurement of potency pA2

Answer 66

-ve log of molar conc. of antagonist that reduces effect of known conc of agonist to that of 1/2 conc. (how good at blocking agonist response) bigger value better antagonist

Question 67

non-competitive antagonists

Answer 67

bind allosteric site or covalently to main site and stay there diff slope gradient and not max response curve none clinically used, but some toxins

Question 68

spare receptors

Answer 68

sometimes don't need to occupy all receptors to get full response (e.g. only 70% needed) use non-competitive antagonists to get full response if still get full response then have spare receptors so conc. for 50% receptors is not conc. for 50% response (Kd not EC50)